Scientia Pharmaceutica Review Remdesivir—Bringing Hope for COVID-19 Treatment 1, , 1, 2, Naser F. Al-Tannak * y, Ladislav Novotny y and Adel Alhunayan y 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait; [email protected] 2 School of Medicine, Health Science Center, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait; [email protected] * Correspondence: [email protected] All authors contributed equally to this work. y Received: 27 May 2020; Accepted: 10 June 2020; Published: 12 June 2020 Abstract: At the beginning of 2020, the world was swept with a wave of a new coronavirus disease, named COVID-19 by the World Health Organization (WHO 2). The causative agent of this infection is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data available on one of the promising therapeutic agents—nucleotide analog remdesivir (Gilead Sciences number GS-5734)—were evaluated. These data were concerned with remdesivir activation from the prodrug to the active molecule—triphosphate containing 10-cyano group and modified nucleobase. This triphosphate competes with the natural substrate adenosine triphosphate. Additionally, its mechanisms of action based on RNA and proofreading exonuclease inhibition, leading to the delayed RNA chain termination of infected cells, and basic pharmacological data were assessed. Additionally, the analytical determination of remdesivir and its metabolites in cells and body liquids and also some data from remdesivir use in other RNA infections—such as Ebola, Nipah virus infection, and Middle East Respiratory Syndrome (MERS)—were summarized. More recent and more detailed data on the clinical use of remdesivir in COVID-19 were reported, showing the intensive efforts of clinicians and scientists to develop a cure for this new disease. Remdesivir as such represents one of the more promising alternatives for COVID-19 therapy, however the current understanding of this disease and the possible ways of dealing with it requires further investigation. Keywords: remdesivir; GS-5734; COVID-19; WHO; RNA-dependent RNA polymerase; endonuclease; RNA viral infections; GS-441524 1. Introduction The year 2020 will be remembered, as at its beginning, a new disease, COVID-19, that is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), affected people around the world [1]. What was first reported as a local event in a city, Wuhan, in China on 31 December 2019 became a Public Health Emergency of International Concern on 30 January 2020, with the first case of this pneumonia reported outside of China in Thailand on 13 January 2020. China confirmed COVID-19 transmission between humans on 20 January. This general development led the World Health Organization (WHO) to declare the infection a pandemic on 11 March 2020 [1]. In the second half of May 2020, over 4.5 million confirmed cases of COVID-19 have been registered around the world, and at least 310,000 COVID-19 patients have succumbed to this disease [2]. As of May 2020, there is a frantic search for suitable therapeutic means to cure this disease. Various drugs have been repurposed for this reason with more or less success. These include lopinavir/ritonavir, favipiravir, darunavir/cobicistat, camostat mesilate/nafamostat, tocilizumab, chloroquine/hydroxychloroquine, colchicine, baricitinib, aviptadil, eculizumab, and remdesivir [3]. As remdesivir is a very promising nucleoside analog originally developed for the treatment of Ebola Sci. Pharm. 2020, 88, 29; doi:10.3390/scipharm88020029 www.mdpi.com/journal/scipharm Sci. Pharm. 2020, 88, 29 2 of 12 disease, the goal of this review is to summarize the current knowledge about remdesivir and its COVID-19Sci. Pharm. 2020 eff,ects. 88, x FOR PEER REVIEW 2 of 12 2.2. MethodMethod ThisThis reviewreview isis based based on on selective selective literature literature searches searches in in PubMed, PubMed, with with remdesivir remdesivir being being always always oneone ofof the the words words that that any any search search was was based based on. on. ThereThere werewere overover 100100 articlesarticles onon thisthis topictopic foundfound onon PubMedPubMed inin MayMay 2020.2020. OtherOther publicpublic domaindomain documentsdocuments andand webweb pagespages (i.e.,(i.e., fromfrom thethe WHO,WHO, CNN,CNN, PubChem,PubChem, etc.) etc.) werewere alsoalso consulted.consulted. 3.3. RemdesivirRemdesivir asas aa ChemicalChemical MoleculeMolecule andand aa ProdrugProdrug RemdesivirRemdesivir was was developed developed as as an an antiviral antiviral agent agent by by the the company company Gilead Gilead Sciences Sciences under under the the name name GS-5734GS-5734 [ 3[3].]. Remdesivir Remdesivir is is a a prodrug prodrug requiring requiring bioactivation bioactivation within within cells. cells. Remdesivir Remdesivir is is aa nucleotide nucleotide 1 analoganalog (Figure(Figure1 1)) with with aa molecularmolecular weightweight 602.585 g·mol g mol−1− andand cumulative cumulative formula formula C27 CH2735HN356ON8P.6O The8P. · TheIUPAC IUPAC (International (International Union Union of ofPure Pure and and Applied Applied Chemistry) Chemistry) name name for for remdesivir isis 2-ethylbutyl2-ethylbutyl (2(2SS)-2-[[[(2)-2-[[[(2RR,3,3SS,4,4RR,5,5RR)-5-(4-aminopyrrolo)-5-(4-aminopyrrolo [2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl] [2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2- methoxy-phenoxyphosphoryl]amino]propanoateyl]methoxy-phenoxyphosphoryl]amino]propanoate (Figure (Figure1)[4 1)]. [4]. FigureFigure 1. 1.The The chemicalchemical formulaformula ofof remdesivirremdesivir ( A(A),), adenosine adenosine 5 50-phosphate′-phosphate ( B(B),), and and of of GS-41524 GS-41524 within within A[A 4[4].]. FeaturesFeatures of of remdesivir remdesivir molecule: molecule: ( A(A)) (1) 1) AmidoAmido substituentsubstituent ofof thethe phosphoricphosphoric acidacid moiety. moiety. It It is is removedremoved during during remdesivir remdesivir activation activati withinon within cells. cells. (2) Phenyl 2) Phenyl substituent substituent of the phosphoricof the phosphoric acid moiety. acid Itmoiety. also is It removed also is removed during remdesivir during remdesivir activation activation within cells. within (3) cells. Cyano 3) groupCyano at group carbon at 1carbon of ribose. 1 of Cyanoribose. group Cyano is notgroup removed is not during removed activation during and activation is an important and is molecularan important feature molecular contributing feature to thecontributing activity of theto the remdesivir activity activeof the metabolite—a remdesivir active triphosphate metabolite—a of nucleoside triphosphate GS-441524. of nucleoside (4) A modified GS- A B nucleobase441524. 4) ofA remdesivir modified ( nucleobase)—compare of to remdesivir the formula of(A adenosine)—compare 50 -monophosphate.to the formula of ( )adenosine According to5′- the IUPAC nomenclature, the name of the nucleobase substituent is 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl-. monophosphate. (B) According to the IUPAC nomenclature, the name of the nucleobase substituent (5) GS-441524—an active nucleoside arising from remdesivir that requires phosphorylation to its is 4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl-. 5) GS-441524—an active nucleoside arising from triphosphate to exhibit its activity. remdesivir that requires phosphorylation to its triphosphate to exhibit its activity. There are several basic molecular features of remdesivir, which is an adenosine nucleotide analog: There are several basic molecular features of remdesivir, which is an adenosine nucleotide (1) As an adenosine nucleotide analog, it compromises RNA synthesis (and not DNA synthesis), analog: 1) As an adenosine nucleotide analog, it compromises RNA synthesis (and not DNA and consequently it is active against RNA viruses. (2) The modification of the phosphate group by the synthesis), and consequently it is active against RNA viruses. 2) The modification of the phosphate substituted amido group increases the lipophilicity of this molecule and forms a prodrug that needs group by the substituted amido group increases the lipophilicity of this molecule and forms a to be activated in the active molecule within the cell through an alanine-substituted intermediate; prodrug that needs to be activated in the active molecule within the cell through an alanine- additionally, the phosphate is also modified by substitution with a phenyl (phenoxy) group that is substituted intermediate; additionally, the phosphate is also modified by substitution with a phenyl (phenoxy) group that is also increasing lipophilicity (see Figure 1). 3) Cyano group at position 1 of ribose of remdesivir and its metabolites and the modified nucleobase of this synthetic nucleoside analog are essential for the disruption of RNA synthesis (Figure 1). Gilead Sciences has given the nucleoside with the cyano substitution and a modified nucleobase the number GS-441524 [4]. The Sci. Pharm. 2020, 88, 29 3 of 12 also increasing lipophilicity (see Figure1). (3) Cyano group at position 1 of ribose of remdesivir and its metabolites and the modified nucleobase of this synthetic nucleoside analog are essential for the disruption of RNA synthesis (Figure1). Gilead Sciences has given the nucleoside with the cyano substitution and a modified nucleobase the number GS-441524 [4]. The active molecule of remdesivir in cells is a triphosphate, with its most important activity being the inhibition of RNA-dependent RNA polymerase [3,5]. The active